This application by a new investigator focuses on the identification of key regulators in skeletal muscle that simultaneously promote the capacity to utilize fat-derived energy and increase the responsiveness to insulin. These two features of healthy metabolism are progressively lost as part of type 2 diabetes pathogenesis. Often, mechanisms that stimulate the use of fat-derived energy in muscle produce resistance to insulin. The overall goal of this proposal is to identify regulatory mediators that increase the capacity of muscle to utilize fat-derived fuel while enhancing sensitivity to insulin. The central hypothesis of this proposal is that PPAR-gamma directly promotes metabolic health in muscle by regulating specific components of lipid metabolism and insulin signaling. Preliminary studies presented herein, using a cell-based model of skeletal muscle, demonstrate that PPAR-gamma directly stimulates the use of fat-derived energy as well as insulin sensitivity. This proposal will employ this model and a newly developed transgenic mouse model in order to dissect the molecular events initiated by PPAR-gamma that lead to the observed improvements in fat utilization and insulin sensitivity. The specific aims of this proposal are to: (1) identify the cellular and molecular mechanisms by which muscle PPAR-gamma promotes lipid metabolism without impeding insulin signaling; (2) identify the cellular mechanisms by which muscle PPAR-gamma promotes insulin sensitivity by dissecting the components of signaling upstream of observed enhancements; and (3) determine the whole-body metabolic consequences of enhanced muscle PPAR-gamma action using a recently-created transgenic model. The therapeutic value of selective activation of PPAR-gamma in muscle will be modeled using a murine model of insulin resistance. PUBLIC HEALTH RELEVANCE: This application, from a new investigator, focuses on identifying molecular regulators that simultaneously promote the use of fat-derived energy and responsiveness to insulin in skeletal muscle. The knowledge gained from the successful completion of this project will help design new strategies to prevent and treat type 2 diabetes onset and progression.